US 2009/0248157 A1 provides a biocompatible substrate for cell adhesion, differentiation, culture and/or growth. The substrate having an arrangement of topographical features arrayed in a pattern based on a notional symmetrical lattice in which the distance between nearest neighbour notional lattice points is C and is between 10 nm and 10 μm. The topographical features are locally miss-ordered such that the centre of each topographical feature is a distance of up to one half of C from its respective notional lattice point.
Cell spreading on a substrate is a highly regulated process that requires the fast interaction between transmembrane receptors of the integrin family and specific ligands on the surface of the substrate (B. Geiger, J. P. Spatz and A. D. Bershadsky, Nat Rev Mol Cell Biol, 2009, 10, 21-33). Early receptor binding leads to onset of spreading and goes along with the enrichment of cytoplasmic proteins at the adhesion site. Here, talin, paxillin, vinculin, and several other proteins contribute to the generation of a nascent focal complex. The recruitment of activated Focal Adhesion Kinase (FAK) and Src-kinase, in turn, forms the basis of adhesion signalling (X. Zhang, G. Jiang, Y. Cal, S. J. Monkley, D. R. Critchley and M. P. Sheetz, Nat Cell Biol, 2008). Small, isotropic focal complexes can mature into larger focal adhesions in a process requiring myosin-II mediated cell contractility and a mechanical linkage with the actin cytoskeleton. On the other hand, insufficient integrin engagement or clustering delays spreading and/or induces cell detachment and eventually apoptosis, thus leading to an incomplete coverage of the target surface (E. A. Cavalcanti-Adam, T. Volberg, A. Micoulet, H. Kessler, B. Geiger and J. P. Spatz, Biophysical journal, 2007, 92, 2964-2974).
Endothelial cells (EC) spread poorly on flat, rigid implant surfaces such as those of commonly used stents for the treatment of the effects of coronary artery disease (S. Garg and P. W. Serruys, J Am Coll Cardiol, 2010, 56, S1-42; M. Hristov, A. Zernecke, E. A. Liehn and C. Weber, Thromb Haemost, 2007, 98, 274-277). Topographic modifications of the surface with micron and sub-micron scale structures may accelerate onset of spreading as well as subsequent topography-guided cell polarization (contact guidance), which are requirements for the re-establishment of a differentiated endothelium. Indeed, surface texturing of known biocompatible materials represents a promising strategy to modulate cellular processes which are essential for the development or regeneration of functional tissues (F. Guilak, D. M. Cohen, B. T. Estes, J. M. Gimble, W. Liedtke and C. S. Chen, Cell Stem Cell, 2009, 5, 17-26; F. Variola, F. Vetrone, L. Richert, P. Jedrzejowski, J. H. Yi, S. Zalzal, S. Clair, A. Sarkissian, D. F. Perepichka, J. D. Wuest, F. Rosei and A. Nanci, Small, 2009, 5, 996-1006). Studies have shown that surface modifications profoundly influence almost all tested cellular activities from cell polarization and migration to gene expression profile, differentiation, and apoptosis (K. Kandere-Grzybowska, C. J. Campbell, G. Mahmud, Y. Komarova, S. Soh and B. A. Grzybowski, Soft Matter, 2007, 3, 672-679; K. Kulangara and K. W. Leong, Soft Matter, 2009, 5, 4072-4076; V. Brunetti, G. Maiorano, L. Rizzello, B. Sorce, S. Sabella, R. Cingolani and P. P. Pompa, Proc Natl Acad Sci USA, 2010, 107, 6264-6269; M. J. Dalby, N. Gadegaard, R. Tare, A. Andar, M. O. Riehle, P. Herzyk, C. D. Wilkinson and R. O. Oreffo, Nat Mater, 2007, 6, 997-1003; J. Z. Gasiorowski, S. J. Liliensiek, P. Russell, D. A. Stephan, P. F. Nealey and C. J. Murphy, Biomaterials, 2010, 31, 8882-8888). However, these studies followed only phenomenological approaches due to the lack of knowledge of the underlying biochemical mechanism. While some insights were provided by works investigating the role of focal adhesion maturation during contact guidance, the effects of topography on cell-to-substrate interaction prior to spreading are still unknown. Fundamental questions remain to be answered, such as whether onset of spreading and contact guidance are independently modulated by the surface topography and whether it is possible to decouple the two processes by pure topographical means.
Thus, beside the tremendous development of stent technology in the last 20 years, there are still some major difficulties which have to be overcome:                Drug eluting stents (DES) are coated with drugs that are gradually released from the stent after implantation and inhibit cell growth. This will reduce significantly the renewed narrowing of the treated vessel, a process known as restenosis. The disadvantage of DES, however is, that they have increased thrombogenicity at blood exposed parts of the incomplete covered stent struts. This so called late stent thrombosis (LST) often proves fatal also after years of implantation and patients have to take blood thinners such as clopidogrel, which renders the treatment very expensive.        Bare metal stents (BMS) are used to unblock occluded arteries and provide a mechanical support to keep the treated vessel open. Normally they show an anti-thrombogenic surface modification and are not coated with active drugs. Thus they are not associated to the same degree with the problem of LST. However, the disadvantage of BMS is, they do not offer any protection against renewed narrowing of the treated vessel, which occurs in 20-30% of all is cases after BMS implantation. This is because after vessel wall injury during stent deployment smooth muscle cells (SMC) inside the arterial wall proliferate much faster than endothelial cells resulting in the formation of neointimal tissue. As a consequence, patients are more likely to undergo repeated surgery to re-open the treated vessel.        Stents with surface microstructures are just under research investigation and no clinical data from human are known today. U.S. Pat. No. 6,190,404 B1 describes for the first time the usage of microgrooves on stent struts for faster healing after stent deployment by favorably modifying endothelial cell (EC) migration. However, these patterns are not optimized for EC migration, proliferation or adhesion, differentiation of circulating precursor cells under flow conditions, whereas it is known that wall shear stress in combination with certain micropattern can have profound effects on cellular behaviour during adhesion, differentiation, migration and proliferation. Moreover other structural design elements like pits and holes in different geometrical arrangements (square, hexagonal, disordered, different heights) were not mentioned in this application but may also play a pivotal role in the development of a functional EC layer (ECL). A similar approach is described in US 2005/0209684 A1.        
The intention of this invention with respect to the case wherein the implant is a stent is therefore to provide a specific geometrical arrangement of surface structures in the sub-micron to micrometer regime for faster re-endothelialization of stent struts after drug eluting stent deployment via Percutaneous Coronary Intervention (PCI). This soft healing approach will significantly reduce the problem of late stent thrombosis (LST) and restenosis.